Neuroblastoma is the most common extra-cranial solid tumor of childhood, and less than 40% of children with high-risk features survive despite intensive treatment. The overall goal of this project is to test novel therapies to improve outcome. Hypothesis: New therapies that are non-cross resistant with standard chemotherapy and have been validated in pre-clinical studies against resistant neuroblastoma will induce responses in patients with refractory tumors. Specific Aims: 1) To establish the maximum tolerated dose (MTD) and, within the confines of a phase I study, to determine efficacy of novel agents with optimal activity against resistant neuroblastoma when used in doses requiring autologous stem cell support (ASCT). 2) To establish the MTD, and activity, of less myelosuppressive agents targeted to neuroblastoma or the microenvironment. 3) To use pre-clinical testing in vitro and in vivo to identify activity in resistant neuroblastoma, and use rational dosing supported by pharmacokinetics, dosimetry or biologic studies. 4) To incorporate specific parameters to quantify bone metastases (semi-quantitative MIBG scan score) and bone marrow disease (immunocytology) into response criteria. Methods and Interactions: Agents developed in Projects 1-3 and validated in pre-clinical studies will be tested in a 14 institution consortium, the NANT (New Approaches to Neuroblastoma Therapy), composed of leading neuroblastoma investigators skilled in Phase I studies, supported by the cores for administration, pathology, digital image scanning microscopy and flow cytometry, small animal models and imaging, and statistics. Agents to be tested, which all have pre-clinical or clinical data to support their use and schedule in neuroblastoma, include 1) agents with ASCT support: buthionine sulfoximine with melphalan, targeted radiotherapy with 131l-metaiodobenzylguanidine in high doses alone or combined with chemotherapy, pyrazoloacridine;and high doses of topotecan and cyclophosphamide 2) less myelosuppressive therapies: CEP-701, a Trk inhibitor;fenretinide, a cytotoxic retinoid;interleukin 12 with pulse IL-2, with immunomodulatory and anti-angiogenic activity;oral combination of protracted irinotecan and temozolamide supported by cefixime;and zoledronic acid, a bisphosphonate, with metronomic cyclophosphamide to inhibit bone metastases. The Scientific Review Committee with input of the preclinical testing facility will prioritize choice of agents. Dosimetry, pharmacokinetics and pharmacodynamics by NANT and Project 1-4 laboratories will ensure that appropriate targeted dosing is achieved. The NANT works in close collaboration with the FDA, CTEP and the Children's Oncology Group to prioritize therapies and bring them into national testing in Phase II and III studies. Significance: These studies will identify promising agents and regimens that are non-cross resistant with current treatments and will result in improved survival for children with high-risk neuroblastoma.